Active Pharmaceutical Ingredients (APIs) are micronized to break down large particles into smaller particles down to the nanometer range, thus improving dissolution and subsequently improving the efficacy of the API. Micronization is performed on the API in a solid state or as a slurry (that is, an API dispersed in a liquid in the presence of a stabilizer). Solid state micronization has limitations on achieving nano size. Usually, slurry state micronization has the advantage of achieving nano Particle Size Distribution (PSD) due to equipment design and the presence of stabilizers (which insures that micronized particles do not grow back to larger particles). But the process becomes extremely challenging when the micronized API is intended for use in sterile formulations, because neither terminal sterilization nor filter sterilization can be performed. As a result, the typical practice is to receive pre-sterilized API, and then prepare a slurry and perform micronization in a tedious sterile environment. It is particularly challenging to operate micronization equipment in a sterile environment, add the pre-sterile API aseptically, and monitor the micronization process progress in a sterile room.
There are several procedures that are currently used in the industry for sterilization of APIs. The most common methods for sterilizing pharmaceutical ingredients are gamma irradiation and ethylene oxide (EO). Other methods include dry heat and steam (autoclave) sterilization. Gamma irradiation generates an electronic beam that upon contact with the exposed product alters various chemical and molecular bonds, including the reproductive cells of microorganisms, thus destroying living organisms. Gamma radiation is characterized by high penetration, low dose rate, and long dwell time. EO sterilization is a chemical process consisting of four primary variables: gas concentration, humidity, temperature, and time. EO is an alkylating agent that disrupts the DNA of microorganisms, which prevents them from reproducing. The EO penetrates and sterilizes all accessible surfaces of the product to render products sterile by alkylation of proteins essential for cell reproduction. If EO is not completely dissipated, then residual amounts of it remain as a contaminant in the pharmaceutical ingredient. Both gamma irradiation and EO cause pharmaceutical ingredients to degrade, resulting in impurities. And heat-based techniques often cause pharmaceutical ingredients to melt. Accordingly, there is a need in the art for improved methods for sterilizing pharmaceutical ingredients, particularly micronized drugs, and for sterilizing Bacitracin.